A role of Miz-1 in Gfi-1-mediated transcriptional repression of CDKN1A

Zinc-finger (ZF) transcriptional repressor growth factor independence 1 (Gfi-1) has an important role in hematopoiesis and inner ear development, and also functions as an oncoprotein that cooperates with c-Myc in lymphomagenesis. Gfi-1 represses transcription by directly binding to conserved sequences in the promoters of its target genes. CDKN1A encoding p21(Cip1) has been identified as a Gfi-1 target gene and has been shown to contain Gfi-1 binding sites in the upstream promoter region. We show here that Gfi-1 represses CDKN1A in a manner that is independent of its DNA binding activity. Gfi-1 interacts with POZ-ZF transcription factor Miz-1, originally shown to be a c-Myc-interacting partner, and through Miz-1 binds to the CDKN1A core promoter. Interestingly, Gfi-1 and c-Myc, through Miz-1, form a ternary complex on the CDKN1A promoter, and function in collaboration to repress CDKN1A. Gfi-1 knockdown results in enhanced levels of p21(Cip1) and attenuated cell proliferation. Notably, similar to c-Myc, the expression of Gfi-1 is downregulated by transforming growth factor-beta (TGFbeta) and the level of Gfi-1 influences the response of cells to the cytostatic effect of TGFbeta. Our data reveal an important mechanism by which Gfi-1 regulates cell proliferation and may also have implications for understanding the role of Gfi-1 in lymphomagenesis.